CCO, ASCO, Medicare, and SEER Analyses
A systematic review focused on stage II patients was conducted by the Cancer Care Ontario (CCO) Program in Evidence-Based Care (PEBC). This review, which included 37 trials and 11 meta-analyses, pooling data from 4,187 patients, found a risk ratio of 0.87 for adjuvant chemotherapy (95% CI = 0.75–1.01, P = .07), representing a trend toward improvement in overall survival.
A separate analysis conducted at the behest of an American Society of Clinical Oncology (ASCO) expert panel tasked with developing recommendations for stage II colon cancer adjuvant therapy limited the analysis to trials with an observation arm and a treatment arm containing 5-FU. Their results also concluded that adjuvant chemotherapy for stage II colon cancer patients does not significantly improve survival (risk ratio = 0.86, P = .08). The authors concluded that there is probably a small benefit for adjuvant treatment that has not been detected as significant because of inadequate trial size.
A different approach was taken using the administrative and registry databases of Medicare and Surveillance, Epidemiology and End Results (SEER) to explore the potential benefits of adjuvant chemotherapy for stage II patients. In that analysis, more than 3,000 patients aged 65 to 75 with stage II colon cancer were identified. Approximately 27% of the patients received adjuvant chemotherapy. This group tended to be younger and in better health and to have a lower tumor grade. After adjustment for available prognostic variables, the hazards ratio for survival associated with adjuvant treatment was found to be 0.91 (95% CI = 0.77–1.09). This analysis was limited, however, by an inability to collect and incorporate confounding prognostic factors (such as obstruction) that may have influenced both the outcomes and the decision to treat with adjuvant chemotherapy.
Our interpretation of the available evidence is that there is likely a small improvement in rates of recurrence and overall survival with adjuvant 5-FU chemotherapy for stage II colon cancer. The benefit has not been demonstrated owing to the inadequate sample sizes of previous studies. Oxaliplatin(Drug information on oxaliplatin) has not demonstrated a benefit in overall survival for stage II patients. This interpretation of the data is influenced by the consistent finding across trials of a similar relative benefit from adjuvant 5-FU chemotherapy for stage II and III patients. Some have suggested that estimates of relative treatment benefit are the best overall measure of treatment effect for stage II patients. Therefore, the identification of high-risk features may define a subset of stage II patients who, as a result of their worse prognosis, may derive a greater absolute benefit from adjuvant treatment.
Toxicity of Chemotherapy in the Stage II Colon Cancer Population
Given the relatively good prognosis of stage II colon cancer patients, a recommendation to administer chemotherapy requires a discussion of the potential risks associated with treatment. The side effects of 5-FU/LV regimens, with or without oxaliplatin, have been well documented in the literature.[16,18] In one recent phase III trial, severe side-effects, defined as grade 3 or higher toxicities, occurred in 14% of stage II patients treated with 5-FU/LV, resulting in premature treatment discontinuation in 6% of patients. The addition of oxaliplatin to the regimen increased these rates (19% of patients experiencing severe adverse events, 12% of which resulted in treatment discontinuation). Although well tolerated in the majority of patients, 5-FU-based regimens can cause severe complications, including death. In most modern trials, rates of treatment-related death range from 0.5% to 1%.[16,18]
The long-term side effects of adjuvant treatment are less well defined. In one study, quality of life decreased after adjuvant 5-FU treatment, requiring up to 1 year to return to baseline levels. The addition of oxaliplatin increases the potential for neurotoxicity, which can significantly affect a patient’s quality of life. This neuropathy can worsen for some time after oxaliplatin is discontinued. Although most oxaliplatin-induced neuropathy resolves over time, it can be an unrelenting symptom in a minority of patients. Neuropathy was still present in 10% of patients 2 years after discontinuation of treatment in the C-07 trial, despite the use of lower cumulative doses of oxaliplatin than in the adjuvant FOLFOX regimen .
Several trials that include patients with stage II disease are incorporating the monoclonal antibodies cetuximab (Erbitux), panitumumab (Vectibix), or bevacizumab(Drug information on bevacizumab) (Avastin) into the adjuvant setting. The toxicities of adjuvant therapy are increased with these biologic agents. For example, bevacizumab is associated with very rare but severe side effects such as arterial thromboembolic events. In addition, the long-term toxicities of these newer agents are not as well defined. Until the risks and benefits of monoclonal agents are better defined, they should not be used in the adjuvant setting.
Risk Stratification in the Stage II Colon Cancer Population
Patients with stage II disease are a heterogeneous population. Understanding the different subgroups of stage II cancer can help determine the appropriate treatment course. For example, stage II patients with T4 primary tumors have a 72% 5-year overall survival rate, which is worse than that of patients with a T2 primary tumor with involvement of fewer than four lymph nodes (83% 5-year overall survival).
While the magnitude of benefit from adjuvant therapy is small for the average stage II patient, it is informative to note that the relative improvement in outcomes with 5-FU adjuvant therapy is similar between stage II and stage III patients (as measured by the hazards ratio or odds ratio). This suggests that the relative benefit of 5-FU may be independent of the absolute risk of recurrence (ie, treatment may result in a 15%–20% relative reduction in recurrence or death regardless of the stage). This finding supports the use of clinical and pathologic variables to further clarify risk of recurrence for stage II tumors, as is suggested by the current guidelines.
However, these recommendations are made on the assumption that the prognostic characteristics will not alter the relative benefit of chemotherapy. Stated another way, it is assumed that these characteristics will not predict response to chemotherapy, but only reflect the risk of recurrence in the absence of treatment. In contrast, predictive markers reflect the response to a particular chemotherapy.
Below, we review the generally accepted prognostic factors, with a brief mention of several nontraditional prognostic factors under investigation. The limitations of prognostic markers and the difficulty in establishing predictive markers will be further discussed below.
Prognostic Pathologic Markers
• T Stage—As noted above, T stage is a major prognostic marker, with T4 tumors having particularly poor outcomes. The T4 classification includes both tumor extension into adjacent structures and perforation of the visceral peritoneum. The median survival of patients with visceral peritoneum involvement has been demonstrated to be significantly shorter than that in patients with tumor extension into adjacent structures. It has been suggested that parietal peritoneum penetration is a worse prognostic factor than nodal involvement, prompting a call for revision of the TNM staging system.
When gross perforation by the primary tumor is present, prognosis is adversely affected not only by the morbidity and mortality associated with the immediate event but also by an apparent increase in the rate of recurrence. Pathologically noted “microperforations” or contained perforations also represent a poor-prognosis subgroup, as is reflected in the current stage II guidelines.[27,35] Similarly, obstruction was found by multivariate analysis to result in 1.6-fold higher odds of recurrence or death within 5 years.
• Lymph Node Evaluation—As part of the TNM staging criteria, lymph node analysis offers clear prognostic information. Interestingly, even for patients without nodal involvement, the number of nodes analyzed is a prognostic factor. A large population-based cohort study from the National Cancer Database evaluated the relationship between the number of lymph nodes resected and overall survival in 35,787 patients. Compared with patients who have 1 to 7 lymph nodes resected, the risk of death was 19% and 32% lower, respectively, for patients with 8 to 12 and more than 13 lymph nodes resected (P < .01).
A systematic review of 61,371 stage II colon cancer patients demonstrated that this finding of improved survival with increased lymph node evaluation was consistent across 16 of the 17 reported trials. This finding has been incorporated into many of the national guidelines for the determination of high-risk stage II colon cancer. Although a cutoff value of 12 resected lymph nodes has been used to distinguish high- and low-risk patients, the degree of risk is continuous in many studies such that, for example, stage II patients with 20 lymph nodes analyzed have better outcomes than those with 15 lymph nodes analyzed.
The association between the number of lymph nodes analyzed and survival not only indicates the importance of adequate mesenteric resection, and of an adequate and thorough evaluation of the specimen by the pathologist, but also a possible biologic relationship with prognostic relevance. When an inadequate number of lymph nodes is reported, medical oncologists should request a pathology reevaluation to ascertain whether additional lymph nodes are present in the submitted tissue, as additional nodes can commonly be identified with diligent gross and/or microscopic examination.
Traditional staging characterizes nodal involvement as groups of tumor cells larger than 0.2 mm. However, smaller groups of cells or isolated tumor cells may also be prognostically informative. Several reports have documented the impact of single cytokeratin-positive cells identified by immunohistochemical (IHC) analysis or carcinoembryonic antigen (CEA) detection in lymph nodes by sensitive polymerase chain reaction (PCR) assays. For example, in a meta-analysis of stage II patients, PCR analysis resulted in the “upstaging” of 37% of the patients, which was associated with a significant decrease in the 3-year overall survival rate (78% vs 97%, P < .001).
Similarly, in a separate study, PCR for cytokeratin 20 was performed to detect hematogenous tumor cell dissemination. These investigators found a strong association between cytokeratin detection and subsequent disease-specific survival in stage II patients (HR = 7.7, P < .001). Although changes in the standard techniques for nodal evaluation are being considered, use of IHC analysis or PCR should be considered investigational and is not yet sufficiently defined to guide clinical care.
• Lymphovascular Invasion—Another histologic feature associated with poor outcomes is the presence of lymphovascular invasion. The term describes the visualization of tumor cells within an endothelial-lined vessel. In a multivariate analysis of over 600 patients, the presence of lymphovascular invasion raised the odds of recurrence 2.8-fold (P < .001). In a separate study, venous invasion combined with T and N stage outperformed the standard TNM staging system as a predictor of individual prognosis. Despite the clear impact of this finding on outcomes, there is significant heterogeneity in the reporting of this risk factor, with high interobserver variation seen. Nevertheless, lymphovascular invasion is considered to be a clinically useful marker of high-risk disease in stage II colon cancer patients.
• Tumor Grade—Another commonly cited prognostic factor, the designation of tumor grade is an attempt to categorize tumor behavior on the basis of architectural and cytologic features, including the extent of gland formation. Although grading systems vary without an accepted standard, most are capable of consistently identifying a subset of poorly differentiated or undifferentiated tumors with a worse prognosis. A large registry study of approximately 80,000 colorectal cancer patients demonstrated 5-year survival rates of 59% and 51%, respectively, for well-differentiated and moderately differentiated tumors, compared to 39% for poorly differentiated tumors.
Similar findings have been reported in stage II patients.[25,46] Mucinous and signet-ring histologies are considered poorly differentiated, and likewise have worse outcomes than well- or moderately differentiated adenocarcinomas. A two-tiered system of well or moderate differentiation vs poor or no differentiation has been adopted for the characterization of tumor risk in adjuvant chemotherapy guidelines for stage II disease.[27,35]
• Other Histologic Markers—Other histologic characteristics, including tumor growth patterns (infiltrating vs expanding), tumor budding on the invasive front, and extent of muscularis invasion, have been shown to be prognostic but not yet applicable to clinical practice.[47,48] Other potential prognostic histology markers are reviewed elsewhere.[33,49]